In retinal vascular disease, in addition to updates on treatment with anti-VEGF drugs, corticosteroids still play a prominent role; results demonstrate the efficacy of various delivery methods with the use of steroids.
Other intriguing subplots, such as nutrition, macular pigment density and imaging, provide insight, and a few other tidbits make this year as interesting and cutting-edge as ARVO has ever been.
Retinal Vascular Disease
Several baseline factors can predict better visual acuity and final OCT outcomes, report the investigators of the SCORE study.3558 This trial evaluated 1mg and 4mg intravitreal triamcinolone injections in patients with macular edema secondary to retinal vein occlusion. Outcomes were assessed at one and two years; researchers measured absolute change of center point thickness from baseline. With both central and branch retinal vein occlusions, researchers found younger patient age to be significantly associated with improved VA and thickness outcomes. Also, less severe anatomical abnormalities of the retina and higher baseline VA letter score at baseline predicted better outcomes in CRVO patients. In BRVO patients, a lack of coronary artery disease, lower baseline VA letter score, dense macular hemorrhage and absence of prior grid photocoagulation predicted better outcomes. What remains to be seen is how intravitreal triamcinolone compares to anti-VEGF therapy, which has emerged as an important treatment option.
Another possible treatment for ME following BRVO or CRVO is ranimibizumab, report the investigators of the BRAVO and CRUISE studies.3561,3566 BRAVO researchers treated 397 patients with ME secondary to BRVO with six monthly injections of 0.3mg ranibizumab, 0.5mg ranibizumab or placebo, and then observed them for another six months. Patients in the control group gained 7.3 letters, the 0.3mg group gained 16.6 letters, and the 0.5mg group gained 18.3 letters. In CRUISE, researchers followed 392 patients with ME secondary to CRVO and also split them into three cohorts; placebo, 0.3mg ranibizumab, and 0.5mg ranibizumab. Control patients gained 0.8 letters, the 0.3mg group gained 12.7 letters and the 0.5mg group gained 14.9 letters. Researchers in both studies noted that patients with worse VA and a baseline central foveal thickness greater than 450µm tended to show higher rates of improvement.
VA decrease due to diabetic macular edema can also be improved with ranibizumab treatment, found the RESOLVE study.5841 Over 12 months, DME patients demonstrated improvement of 7.8 letters (pooled) vs. -0.1 in the placebo group.
But, how long can patients stay on such a treatment regimen? Two years of treatment for DME with ranibizumab appears safe and results in VA improvement, report investigators on the READ 2 study.5842 Patients in this study were treated with a combination of focal laser and ranibizumab, and results ranged from 7.6 to 5.0 letters gained in VA at two years.
Macular edema can be managed with the Ozurdex intravitreal dexamethasone implant (Allergan), found researchers in Chicago.4722 Patients with ME secondary to retinal vein occlusion were injected and followed at one week, one month and three months. Preliminary data show that, at one week, average central subfield thickness decreased by 408µm and VA improved by one to two lines. Final results have yet to be released, but this is a promising therapy.
Clearly, there are now more treatment options for patients with retinal vascular disease then ever before. For CRVO patients with macular edema, these treatments are especially important—before the advent of steroids and anti-VEGF drugs, no treatment successfully improved vision. What remains to be seen, however, is which treatment will emerge as the definitive choice for clinicians. For diabetic macular edema and BRVO with macular edema, how will these treatments compare to the gold standard of laser photocoagulation? Only time will tell.
How Likely Is a Second Malignancy?
In patients whose retinoblastoma was treated with chemoreduction,
long-term occurrence of second non-ocular malignancy was low, found
researchers in Philadelphia.4763
Out of 272 patients who had been treated for retinoblastoma with chemoreduction, only 2.2% experienced a second malignancy. But, of the 181 patients within the total group who had germline mutations, nearly 3.3% experienced a second malignancy. All six of these patients demonstrated bilateral sporadic retinal blastoma. Bottom line: At 10 years, second malignancy only occurs in a small percentage of patients, and this chance can be increased slightly due to germline mutation or additional radiotherapy.
Hydroxychloroquine Toxicity Odds Increase with Duration
HCQ toxicity is uncommon, but odds increase with duration of therapy
and cumulative dosage, report researchers in Kansas.4324 Study authors
searched the 3,995 patients in the National Data Bank for Rheumatic
Disease for those who self-reported toxicity and followed up on these
cases with interviews and eye care practitioner confirmation. Cases
that included bull’s eye maculopathy or perifoveal visual field loss
were categorized as “probable or definite.” Of these lifetime users,
6.5% discontinued therapy because of an eye problem, including 1.8% who
reported retinal complications. Risk of toxicity was found to be lower
in the initial few years of exposure (0.2% to 0.3%), but then it
quintupled after seven years of cumulative usage. After 20 years, risk
neared 3%. Toxicity was found to be unrelated to age, weight or daily
dose per kilogram.
AMD
Anti-VEGF therapy has emerged as the treatment of choice for neovascular AMD. But, what if AMD could be stopped earlier in its development? AMD treatment currently focuses on VEGF inhibition; when you stop treatment with the drug, the disease resurges. But, VEGF is a necessary component of the eye, and long-term side effects aren’t known. So, researchers in Maryland are looking earlier in the disease process to block AMD progression.3505 In cultures of human adult RPE cells, complement fragment C5a was found to decrease RPE cell viability, which, researchers note, may explain the geographic atrophy found in dry AMD. C5a down-regulated certain chemokine receptors, leading to dysfunction of leukocyte trafficking and lessening of macular debris elimination. Bottom line, say researchers: C5a may play a significant role in the pathogenesis of AMD, and should be examined more closely.
Researchers in Durham, N.C., found that a combination of VEGF and C5 inhibition in cases of neovascular AMD was well tolerated, with no evidence of acute toxicity.1251 Patients were given escalating doses of the aptamer ARC1905, which inhibits complement factor 5 (a part of complement factor H), in combination with ranibizumab. The mean change in visual acuity was an increase of 10.5 letters.
Likewise, what if the amount of drusen could be managed or even decreased, slowing the patient’s progression? Researchers in New York injected either the new drug Copaxone (glatiramer acetate, Teva Pharmaceutical Industries) or sham in eyes of patients with dry AMD for 12 weeks. At 12 weeks, drusen in the eyes of those treated with Copaxone had shrunk by 19.1% vs. only 6.5% in the sham group.
As new drugs emerge to treat AMD earlier, it will be important to accurately monitor disease progression as well as the response to these novel treatments. Researchers in Germany, Texas and North Carolina posit that identification of lesion characteristics can benefit future therapeutic research.94/A141 They aimed to determine the rate of progression of geographic atrophy lesions with fundus autofluorescence imaging and assess baseline characteristics that could predict lesions’ growth rates. The researchers found that growth rates significantly correlated with baseline size, location and complexity. Uni- or bilaterality had no impact. Diffuse lesion patterns also indicated greater lesion enlargement rates.
What Gene Causes MacTel?
The MacTel project aims to determine the genetic cause of macular
telangiectasia.1656/A32 Affected individuals, their family members and
control patients are being recruited at 26 centers in seven countries.
Currently, cohorts stand at 332 control patients and 240 family-linked
patients. Researchers performed genome-wide linkage analysis and
determined a group of MacTel candidates. Of these, they limited the
field to three: those with peaks on chromosomes 7, 10 and 12.
What’s the next step? Researchers need to evaluate these peaks in detail via haplotype analysis, and follow-up research includes association analysis and exome sequencing.
Sleep Apnea Signals PDR
Obstructive sleep apnea (OSA) is 16 times more common in patients who
have type 2 diabetes and macular edema, found researchers in the United
Kingdom.4257/D923 Of the 58 patients studied, 37 patients (63.8%) had
OSA, as opposed to 4% in the general population. And, 10 of these 37
vs. only two of the remaining 21 had progressive diabetic retinopathy
(PDR). So, researchers concluded that not only is OSA more common in
patients with type 2 diabetes, but also that within this group, it is
associated with a higher incidence of PDR.
Nutraceuticals
What do the patients taking part in AREDS2 look like?97/A144 Of the 4,203 patients, mean age is 73 (range: 50 to 80), 57% are female, 97% are white and 65% have two eyes involved in the study. Mean VA is 79±11 letters. Dietary DHA and EPA intake is inversely related to AMD score. At baseline, participants have good visual function in their study eye(s), and the majority have risk factors for progression to advanced AMD. Even at baseline, those patients reporting a high intake of DHA or EPA were likely to have less severe AMD than other patients.
In another study looking specifically at the effect zeaxanthin and lutein supplements on macular pigment optical density, investigators in Chicago found that early AMD patients who take zeaxanthin supplements demonstrate macular pigment optical density (MPOD) equal to that due to lutein supplementation.510/A156 Over the course of one year, patients either took zeaxanthin, lutein or placebo. There were no differences due to age, smoking or body-mass index. MPOD rose in each group at about the same rate; however, those patients in the zeaxanthin group showed significantly better foveal shape discrimination, and they were more likely to experience partial or complete clearing of their central scotoma.
Another group of researchers specifically examined meso-zeaxanthin alongside zeaxanthin and lutein in an attempt to determine the most effective formulation.514/A160 In the Meso-Zeaxanthin Ocular Supplementation Trial (MOST), researchers divided patients into groups, which then received either a meso-zeaxanthin-heavy formulation or placebo. They found that the meso-zeaxanthin seemed to have the greatest effect, increasing MPOD at the center 0.25º of the macula.
A growing body of evidence supports the ability to modify MPOD via supplements. There is more to be done; such studies continue to show us that supplements could quite even possibly become an important treatment option for AMD.
But, when testing macular function, test-retest variability and measurement analysis need to be uniform to ensure accurate data collection. Researchers in Rome tested outcome measures for test-retest variability in a clinical research setting: number of letters read to contrast sensitivity testing with Pelli-Robson charts; amplitude of the pattern-reversal electroretinogram at 100% contrast, black and white; dark-adapted foveal cone sensitivity at 650nml and parafoveal rod sensitivity at 500nm, as measured by Humphrey perimeter.2801/D839 Results indicated that all of these methods demonstrate excellent test-retest variability and seem very well suited for studies of macular function and response.
Is Telemedicine Effective?
Yes, found researchers in Boston.4676/D951 Among patients who receive
diabetes care at a tertiary diabetes-specific academic medical center,
an ocular telemedicine program successfully identified and promoted eye
care for a large, substantially different cohort from that already
receiving regular care at the center. These patients tended to be
younger, were more likely minority, and exhibited less severe diabetes
and/or retinopathy.
The telemedicine program imaged 7,358 total patients, and 3,449 of these were referred to and examined at the eye care clinic. So, researchers found, even in a tertiary-care diabetes-specific clinic, the telemedicine program enhanced access to appropriate care for patients who can benefit greatly from medical management.
Lucentis vs. Avastin: Injection Trends
Researchers in Florida found that, out of a total 11,398 intravitreal
anti-VEGF injections administered between July 2006 and November 2009,
bevacizumab use increased in frequency while ranibizumab use
decreased.538/A219 Intravitreal ranibizumab accounted for 85% of
injections in 2006, 40% in 2007, 25% in 2009 and 21% in 2009.
Specifically, November 2009 accounted for 20% of that year’s total.
On the other hand, annual bevacizumab injections increased from 22% of total anti-VEGF injections in 2006 to 80% in 2009.
Researchers note that ranibizumab’s entry into the market in 2006 accounts for the high percentage of utilization that year, and that the subsequent increase in use of bevacizumab over the course of the following years reflects the influence of direct drug costs, increased patient volume and potential reimbursement changes during this time period.
Imaging
Imaging has come a long way since David Huang, M.D., Ph.D., conceived the idea of the OCT in the early 1990s. How far can this envelope be pushed? What could we learn about a condition if we could accurately see all of its effects?
Researchers developed a novel way to examine the interior of the eye—by projecting it within a 3-D, stereoscopic, immersive virtual reality environment (CAVE) that allows the user to stand within the image and explore it.1006/A569 CAVE users can view, manipulate and interact with volumetric and slice-based high-resolution SD-OCT images in 3-D space. Researchers developed a method to interpret raw data from SD-OCT for visualization within the CAVE. Data of rendered images of AMD, central serous chorioretinopathy, retinal detachment and vitreomacular traction were read into scalar fields, analyzed and filtered into CAVE. Researchers note that future customization will allow users to isolate structures and enhance understanding of disease pathology.
How could ultra-high speed OCT imaging improve disease diagnosis and management? It provides comprehensive and high-resolution visualization of the retina, say researchers, which in turn can improve disease detection and monitoring.1017/A580 Current OCT systems have 5µm axial resolution and operate at up to 52,000 axial scans per second. But, prototype ultra-high speed spectral/Fourier domain OCT technology that operates at 800nm and 1050nm took 70,000 to 312,500 scans per second and 50,000 to 200,000 scans per second, respectively. Dense 3D-OCT data sets showed minimal motion artifacts and improved image continuity.
SD-OCT with autofluorescence can be used intraoperatively for pediatric patients with complex retinal disease, found researchers in Florida.3861 Fifteen pediatric patients with retinal blastoma underwent exam with anesthesia. SD-OCT with eye-tracking capabilities allowed practitioners to take high-resolution images of the macula and off-axis peripheral lesions. Total imaging time averaged five minutes. This technique allows for progressive, consistent evaluation of specific retinal locations.
